Fungal infection is a major healthcare problem, and the incidence of hospital-acquired fungal diseases continues to rise. Severe systemic fungal infection in hospitals (such as candidiasis, aspergillosis, histoplasmosis, blastomycosis and coccidioidomycosis) is commonly seen in neutropaenic patients following chemotherapy and in other oncology patients with immune suppression, in patients who are immune-compromised due to Acquired Immune Deficiency Syndrome (AIDS) caused by HIV infection, and in patients in intensive care. Systemic fungal infections cause about 25% of infection-related deaths in leukaemics. Infections due to Candida species are the fourth most important cause of nosocomial bloodstream infection. Serious fungal infections may cause 5 to 10% of deaths in patients undergoing lung, pancreas or liver transplantation. Treatment failures are still very common with all systemic mycoses. Secondary resistance also arises. Thus, there remains an increasing need for effective new therapy against mycotic infections and for processes for isolating and purifying compounds useful in such therapy.
Enfumafungin is a hemiacetal triterpene glycoside that is produced in fermentations of a Hormonema spp. associated with living leaves of Juniperus communis. See U.S. Pat. No. 5,756,472; Fernando Peláez et al., The Discovery of Enfumafungin, a Novel Antifungal Compound Produced by an Endophytic Hormonema Species Biological Activity and Taxonomy of the Producing Organisms, 23 SYSTEM. APPL. MICROBIOL. 333 (2000); Robert E. Schwartz et al., Isolation and Structural Determination of Enfumafungin, a Triterpene Glycoside Antifungal Agent That Is a Specific Inhibitor of Glucan Synthesis, 122 J. AM. CHEM. SOC. 4882 (2000); Robert E. Schwartz, Cell wall active antifungal agents, 11(11) EXPERT OPIN. THER. PATENTS 1761 (2001). Enfumafungin is one of the several triterpene glycosides that have in vitro antifungal activities. The mode of the antifungal action of enfumafungin and other antifungal triterpenoid glycosides was determined to be the inhibition of fungal cell wall glucan synthesis by their specific action on (1,3)-β-D-glucan synthase. See J. Onishi et al., Discovery of Novel Antifungal (1,3)-β-D-Glucan Synthase Inhibitors, 44(2) ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 368 (2000); Pelaez et al., Systematic and Applied Microbiology, 23:333-343, 2000). 1,3-β-D-Glucan synthase remains an attractive target for antifungal drug action because it is present in many pathogenic fungi that affords broad antifungal spectrum and because there is no mammalian counterpart. As such, these compounds have little or no mechanism-based toxicity.
Because of the desirability of glycan synthase inhibitors as antifungal agents, there is a need for cost-effective processes for isolating and purifying enfumafungin and other natural products, both for use as antifungal agents and/or glycan synthase inhibitors and for use as intermediates for the preparation of other compounds that can be used as antifungal agents and/or glycan synthase inhibitors.